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Molecular Mechanisms of Psilocybin and Implications for the Treatment of Depression

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Abstract

Therapeutic deficiencies with monoaminergic antidepressants invites the need to identify and develop novel rapid-acting antidepressants. Hitherto, ketamine and esketamine are identified as safe, well-tolerated rapid-acting antidepressants in adults with treatment-resistant depression, and also mitigate measures of suicidality. Psilocybin is a naturally occurring psychoactive alkaloid and non-selective agonist at many serotonin receptors, especially at serotonin 5-HT2A receptors, and is found in the Psilocybe genus of mushrooms. Preliminary studies with psilocybin have shown therapeutic promise across diverse populations including major depressive disorder. The pharmacodynamic mechanisms mediating the antidepressant and psychedelic effects of psilocybin are currently unknown but are thought to involve the modulation of the serotonergic system, primarily through agonism at the 5-HT2A receptors and downstream changes in gene expression. It is also established that indirect effects on dopaminergic and glutamatergic systems are contributory, as well as effects at other lower affinity targets. Along with the direct effects on neurochemical systems, psilocybin alters neural circuitry and key brain regions previously implicated in depression, including the default mode network and amygdala. The aim of this review is to synthesize the current understanding of the receptor pharmacology and neuronal mechanisms underlying the psychedelic and putative antidepressant properties of psilocybin.

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Authors and Affiliations

  1. Mood Disorders Psychopharmacology Unit, Poul Hansen Family Centre for Depression, University Health Network, 399 Bathurst Street, MP 9-325, Toronto, ON, M5T 2S8, Canada

    Susan Ling, Felicia Ceban, Leanna M. W. Lui, Yena Lee, Kayla M. Teopiz, Nelson B. Rodrigues, Orly Lipsitz, Hartej Gill, Mehala Subramaniapillai, Rodrigo B. Mansur, Joshua D. Rosenblat & Roger S. McIntyre

  2. Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON, Canada

    Susan Ling & Roger S. McIntyre

  3. Department of Psychiatry, University of Toronto, Toronto, ON, Canada

    Rodrigo B. Mansur, Joshua D. Rosenblat, David Castle & Roger S. McIntyre

  4. Department of Psychological Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore

    Roger Ho

  5. Institute for Health Innovation and Technology (iHealthtech), National University of Singapore, Singapore, Singapore

    Roger Ho

  6. Centre for Addiction and Mental Health, Toronto, ON, Canada

    David Castle

  7. Department of Affective Disorders, The Affiliated Brain Hospital of Guangzhou Medical University, (Guangzhou Huiai Hospital), Guangzhou Medical University, Guangzhou, China

    Kangguang Lin

  8. Laboratory of Emotion and Cognition, The Affiliated Brain Hospital of Guangzhou Medical University (Guangzhou Huiai Hospital), Guangzhou Medical University, Guangzhou, China

    Kangguang Lin

  9. Brain and Cognition Discovery Foundation, Toronto, ON, Canada

    Felicia Ceban, Yena Lee & Roger S. McIntyre

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  1. Susan Ling
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Correspondence to Roger S. McIntyre.

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Conflicts of interest

Dr. Roger McIntyre has received research grant support from CIHR/GACD/Chinese National Natural Research Foundation; speaker/consultation fees from Lundbeck, Janssen, Purdue, Pfizer, Otsuka, Takeda, Neurocrine, Sunovion, Bausch Health, Novo Nordisk, Kris, Sanofi, Eisai, Intra-Cellular, NewBridge Pharmaceuticals, Abbvie. Dr. Roger McIntyre is a CEO of Braxia Scientific Corp. Dr. Joshua D. Rosenblat is the medical director of the Braxia Health (formally known as the Canadian Rapid Treatment Center of Excellence and is a fully owned subsidiary of Braxia Scientific Corp) which provides ketamine and esketamine treatment for depression; he has received research grant support from the American Psychiatric Association, the American Society of Psychopharmacology, the Canadian Cancer Society, the Canadian Psychiatric Association, the Joseph M. West Family Memorial Fund, the Timeposters Fellowship, the University Health Network Centre for Mental Health, and the University of Toronto and speaking, consultation, or research fees from Allergan, COMPASS, Janssen, Lundbeck, and Sunovion. Dr. Yena Lee is an employee of Braxia Scientific Corp. Leanna M.W. Lui has received: personal fees from Braxia Scientific Corp and honoraria Medscape. Kayla M. Teopiz has received personal fees from Braxia Scientific Corp. All other authors declare no conflicts of interest and/or financial disclosures.

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SL, FC, and RSM drafted the manuscript. All authors provided critical feedback and revisions, approved the final manuscript, and agreed to be accountable for the work.

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Ling, S., Ceban, F., Lui, L.M.W. et al. Molecular Mechanisms of Psilocybin and Implications for the Treatment of Depression. CNS Drugs 36, 17–30 (2022). https://doi.org/10.1007/s40263-021-00877-y

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